Agonists to ions: Efficiency suggests a 'zipper' mechanism for nicotinic receptor activation

Mapping Intimacies ◽

10.1101/2021.12.18.473297 ◽

2021 ◽

Author(s):

Anthony Auerbach

Keyword(s):

Binding Energy ◽

Nicotinic Receptor ◽

Receptor Activation ◽

Agonist Binding ◽

Response Curves ◽

Nicotinic Acetylcholine ◽

Turn On ◽

Activation Gating ◽

Target Sites ◽

Agonist Property

Agonists are classified by the strength at which they bind to their target sites (affinity) and their ability to activate receptors once bound to those sites (efficacy). Efficiency is a third fundamental agonist property that is a measure of the correlation between affinity and efficacy. Efficiency is the percent of agonist binding energy that is converted into energy for receptor activation ('gating'). In the muscle nicotinic acetylcholine receptor, agonists belong to families having discrete efficiencies of 54%, 51%, 42% or 35%. Efficiency depends on the size and composition of both the agonist and binding site, and can be estimated from, and used to interpret, concentration-response curves. A correlation between affinity and efficacy indicates that the agonist's energy changes that take place within binding and gating processes are linked. Efficiency suggests that receptors turn on and off by progressing through a sequence of energy-linked domain rearrangements, as in a zipper.

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A single molecular distance predicts agonist binding energy in nicotinic receptors

The Journal of General Physiology ◽

10.1085/jgp.201812212 ◽

2019 ◽

Vol 151 (4) ◽

pp. 452-464 ◽

Cited By ~ 3

Author(s):

Sushree Tripathy ◽

Wenjun Zheng ◽

Anthony Auerbach

Keyword(s):

Binding Energy ◽

Acetylcholine Receptors ◽

Structural Parameters ◽

Aromatic Amino Acids ◽

Binding Pocket ◽

Binding Energies ◽

Agonist Binding ◽

Response Curves ◽

Dynamics Simulations ◽

Experimental Binding Energy

Agonists turn on receptors because they bind more strongly to active (R*) versus resting (R) conformations of their target sites. Here, to explore how agonists activate neuromuscular acetylcholine receptors, we built homology models of R and R* neurotransmitter binding sites, docked ligands to those sites, ran molecular dynamics simulations to relax (“equilibrate”) the structures, measured binding site structural parameters, and correlated them with experimental agonist binding energies. Each binding pocket is a pyramid formed by five aromatic amino acids and covered partially by loop C. We found that in R* versus R, loop C is displaced outward, the pocket is smaller and skewed, the agonist orientation is reversed, and a key nitrogen atom in the agonist is closer to the pocket center (distance dx) and a tryptophan pair but farther from αY190. Of these differences, the change in dx shows the largest correlation with experimental binding energy and provides a good estimate of agonist affinity, efficacy, and efficiency. Indeed, concentration–response curves can be calculated from just dx values. The contraction and twist of the binding pocket upon activation resemble gating rearrangements of the extracellular domain of related receptors at a smaller scale.

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Agonist efficiency estimated from concentration-response curves

10.1101/2020.10.13.337410 ◽

2020 ◽

Author(s):

Dinesh C. Indurthi ◽

Anthony Auerbach

Keyword(s):

Binding Energy ◽

Binding Site ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Head Group ◽

Constitutive Activity ◽

High Concentration ◽

Response Curves ◽

Nicotinic Acetylcholine ◽

Low Efficiency

AbstractConcentration-response curves (CRCs) are characterized by a midpoint (EC50) and a high-concentration asymptote (Pomax) that relate to agonist affinity and efficacy. A third agonist attribute, efficiency, is the fraction of binding energy that is applied to the conformational change that activates the receptor. Here we show that agonist efficiency can be calculated from EC50 and Pomax, and estimate the efficiencies of 17 agonists of adult muscle nicotinic acetylcholine receptors (AChRs). The distribution of efficiency values was bi-modal with means+s.d of 52±2% (n=11) and 41±3% (n=6). Efficiency is correlated inversely with the volume of the agonists’ head-group. For 22 binding site mutations only αY190A affects significantly ACh efficiency, switching it from the high-to the low-efficiency population. If agonist efficiency is known, EC50 can be estimated from Pomax and the receptor’s level of constitutive activity can be calculated from a CRC.

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Faculty Opinions recommendation of Alpha7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioural changes in a modified continuous Y-maze task in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1146929.604026 ◽

2009 ◽

Author(s):

Jerry Buccafusco

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Receptor Activation ◽

Maze Task ◽

Nicotinic Acetylcholine ◽

Alpha7 Nicotinic Acetylcholine Receptor ◽

Behavioural Changes ◽

Y Maze

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Structure of the agonist-binding site of the nicotinic acetylcholine receptor. [3H]acetylcholine mustard identifies residues in the cation-binding subsite.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)54504-x ◽

1991 ◽

Vol 266 (34) ◽

pp. 23354-23364

Author(s):

J.B. Cohen ◽

S.D. Sharp ◽

W.S. Liu

Keyword(s):

Binding Site ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Cation Binding ◽

Agonist Binding ◽

Nicotinic Acetylcholine

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Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs

Biology ◽

10.3390/biology10020167 ◽

2021 ◽

Vol 10 (2) ◽

pp. 167

Author(s):

Jaana Künnapuu ◽

Honey Bokharaie ◽

Michael Jeltsch

Keyword(s):

Growth Factors ◽

Molecular Level ◽

Specific Antigen ◽

Receptor Activation ◽

Vascular Endothelial Growth Factors ◽

Vascular Endothelial ◽

Turn On ◽

C And N ◽

Proteolytic Cleavages ◽

Endothelial Growth Factors

Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymphangiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the “mature” growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer.

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